Scientists are searching for new medications, possible causes and potential risk factors for this autoimmune disease.

By Susan Bernstein

Rheumatoid arthritis (RA), an autoimmune disease affecting as many as 1.5 million Americans, has been the focus of intense and fruitful research over the past two decades. A number of effective treatments for RA have been approved by the FDA for treating this disease, including a category of disease-modifying antirheumatic drugs (DMARDs) called biologic response modifiers (biologics), which are designed to halt the internal processes that cause inflammation.

While the biologic drugs currently approved for RA have shown great effectiveness in controlling inflammation and preventing the joint erosion and deformity that characterize this condition, they carry many side effects and risks, including a greater likelihood of developing serious infections. While some researchers are seeking new, more effective and safer treatments for RA, others are investigating possible causes or working to identify potential risk factors for developing the disease.

Fighting RA With Antibodies

One active area of RA research and development focuses on antibodies, proteins made by the body’s immune system that identify disease-causing agents for destruction. Several antibodies are already approved by the FDA for use in RA treatment, but new ones are being studied for effectiveness. Antibody treatments are typically given as injections or infusions.

Denosumab (Prolia) targets a molecule called RANKL, a cytokine, or protein that can play a part in RA inflammation. The first RANKL inhibitor approved by the FDA (for osteoporosis and bone-related problems in cancer), denosumab is being studied for RA use. A study published in the journal Arthritis Care & Research last spring showed the drug’s effectiveness in preventing bone erosion and improving hand bone mineral density in 56 RA patients already taking methotrexate.
Gevokizumab, an antibody that inhibits IL-1ß, a cytokine that at high levels could trigger inflammation, is currently in Phase II clinical trials after early studies showed it was potentially effective and well tolerated as an RA treatment.

Ofatumumab (Arzerra), already approved for treating a form of leukemia, is an anti-CD20 monoclonal antibody now being studied for RA use. (Monoclonal simply means the antibody comes from a single parent cell; CD20 is a protein.) A two-part, Phase I and Phase II study showed the drug was effective in RA patients whose disease did not respond to other DMARDs.

Otelixizumab, an anti-CD3 antibody (targeting the antigen CD3), is currently in a Phase II clinical trial to study its safety and tolerability in a small group of RA patients, as well as its effectiveness compared with adalimumab (Humira). The drug is in more advanced studies as a type-1 diabetes treatment.

Clinical trials for ocrelizumab, an anti-CD20 antibody, were halted in March 2010 due to participants developing serious infections that caused several deaths.

Rheumatoid arthritis (RA), an autoimmune disease affecting as many as 1.5 million Americans, has been the focus of intense and fruitful research over the past two decades. A number of effective treatments for RA have been approved by the FDA for treating this disease, including a category of disease-modifying antirheumatic drugs (DMARDs) called biologic response modifiers (biologics), which are designed to halt the internal processes that cause inflammation.

While the biologic drugs currently approved for RA have shown great effectiveness in controlling inflammation and preventing the joint erosion and deformity that characterize this condition, they carry many side effects and risks, including a greater likelihood of developing serious infections. While some researchers are seeking new, more effective and safer treatments for RA, others are investigating possible causes or working to identify potential risk factors for developing the disease.

Fighting RA With Antibodies

One active area of RA research and development focuses on antibodies, proteins made by the body’s immune system that identify disease-causing agents for destruction. Several antibodies are already approved by the FDA for use in RA treatment, but new ones are being studied for effectiveness. Antibody treatments are typically given as injections or infusions.

Denosumab (Prolia) targets a molecule called RANKL, a cytokine, or protein that can play a part in RA inflammation. The first RANKL inhibitor approved by the FDA (for osteoporosis and bone-related problems in cancer), denosumab is being studied for RA use. A study published in the journal Arthritis Care & Research last spring showed the drug’s effectiveness in preventing bone erosion and improving hand bone mineral density in 56 RA patients already taking methotrexate.
Gevokizumab, an antibody that inhibits IL-1ß, a cytokine that at high levels could trigger inflammation, is currently in Phase II clinical trials after early studies showed it was potentially effective and well tolerated as an RA treatment.

Ofatumumab (Arzerra), already approved for treating a form of leukemia, is an anti-CD20 monoclonal antibody now being studied for RA use. (Monoclonal simply means the antibody comes from a single parent cell; CD20 is a protein.) A two-part, Phase I and Phase II study showed the drug was effective in RA patients whose disease did not respond to other DMARDs.

Otelixizumab, an anti-CD3 antibody (targeting the antigen CD3), is currently in a Phase II clinical trial to study its safety and tolerability in a small group of RA patients, as well as its effectiveness compared with adalimumab (Humira). The drug is in more advanced studies as a type-1 diabetes treatment.

Clinical trials for ocrelizumab, an anti-CD20 antibody, were halted in March 2010 due to participants developing serious infections that caused several deaths.

JAK and SYK Inhibitors:
Controlling Immune System Signals

A kinase is an enzyme in the body involved in immune system functions. In diseases like RA, various pathways or signals between key cells can function abnormally, so researchers are looking at new treatments that may inhibit or “turn off” these improper signals.

Tofacitinib (Xeljanz) is an oral medicine approved by the FDA to treat RA in 2012. It’s intended to stop the Janus Associated Kinase, making it a JAK-inhibitor.

Researchers working on another drug, SB1578, reported favorable results in inhibiting the kinase JAK-2 at the annual ACR meeting in November. An early study of rats with RA treated with SB1578 showed the drug helped normalize cytokine levels. It is now involved in clinical trials recruiting human patients.

In addition to JAK inhibitors, investigators are also working on inhibiting the spleen tyrosine kinase (SYK). A Phase II study of the oral SYK-inhibitor fostamatinib reported in The New England Journal of Medicine in 2010 focused on 457 patients with active RA taking methotrexate as well. Around two-thirds of the patients showed significantly reduced disease activity by adding fostamatinib daily. A new clinical trial of the drug comparing it to adalimumab (Humira) treatment for RA patients is currently recruiting participants.

More Ways to Control Rheumatoid Arthritis

Vitamin D, which the body absorbs through sun exposure and from foods like fish or fortified milk, is being studied for many health benefits. Vitamin D helps the body absorb and maintain levels of calcium. A group of U.S. and Canadian scientists published a study in 2010 that examines the benefits of intensive vitamin D therapy for RA patients. Many people with RA test low for vitamin D levels in their blood. This study of 89 RA patients showed that to maintain normal levels of vitamin D, people with RA may need to take much higher doses of supplements than the rest of the population.

Statins, a group of drugs widely used for lowering cholesterol and preventing heart disease, are being studied for their effectiveness in fighting inflammation and autoimmunity. An Israeli study published in 2010 showed that statin use may lower the risk of developing RA.

One group of researchers in California is working on a drug called ASP2408 that aims to decrease the production of inflammation-causing T-cells in RA more effectively. Part of a group of treatments called CTLA4-Ig therapies, which includes the RA drug abatacept (Orencia), this drug is in a Phase I clinical trial now.

Early Detection Strategies for RA

Scientists are investigating possible clues to the development of RA, as well as better methods for detecting the disease as early as possible. At the ACR’s 2010 Annual Meeting, which was held in Atlanta in November, significant milestones in this effort were announced.

Could fat play a role of RA inflammation? Adipose tissue, or body fat, serves as an energy store for the body, but also produces cytokine-like cells called adipokines that may promote inflammation in RA. German researcher Ulf Müller-Ladner, MD, spoke about his research on the connection between adipose tissue and RA inflammation at the ACR’s Annual Meeting. He noted that adipokine levels are higher in people with RA, and that some existing RA therapies, such as TNF-inhibitors, may help suppress these cells.

At least five genes have been identified that seem to be associated with RA development, said researchers at the ACR Basic Science Symposium. But how does a person with the gene develop RA? Likely through environmental factors, such as smoking or contracting an infection. People with higher anti-cyclic citrullinated protein antibody (ACPA) levels in the body are at higher risk of developing RA, the scientists noted. One study in Manitoba is examining Native American tribes with high rates of RA to learn more about the ACPA-RA connection.

Doppler Ultrasonography (DUS), used in many medical settings, is being refined and studied for use in tracking the effectiveness of RA treatments by measuring inflammation in the joints, like synovitis. Newer, high-resolution ultrasound imaging techniques like DUS can help doctors evaluate disease activity more effectively.

Doctors once thought RA was an infectious disease, and treated it with antibiotics like minocycline. While we now know otherwise, scientists are revisiting the RA-infection connection. The opening lecturer at the ACR’s 2010 Annual Meeting, Gerald Weissmann, MD, of New York University, spoke about his current research on whether the bacteria causing gingivitis, or gum disease, may cause or trigger RA in people with genes that predispose them to the disease.

Another lecturer addressed the similarity between joint and gum inflammation and noted that oral inflammation is common and often severe in people with RA. Clifton Bingham III, MD, of Johns Hopkins University Arthritis Center, discussed how early recognition of periodontal disease may help doctors spot RA earlier, and quitting smoking, improving oral hygiene, and use of antibiotics may be helpful interventions.

Clinical trials looking at the role of bacteria in RA development are under way, involving both medical and dental researchers.

While a diagnosis of RA is certainly a life-altering event, there has never been a more promising time when it comes to developing new ways to stop disease progression, prevent joint damage and enhance the quality of life for those affected.